Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin-induced hemolytic-uremic syndrome in mice.
Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin-induced hemolytic-uremic syndrome in mice.
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DOI：
10.1016/j.kint.2021.12.024
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发表时间：
2022-01
影响因子：
19.6
通讯作者：
Wiebke Pirschel;Antonio N. Mestekemper;B. Wissuwa;N. Krieg;Sarah Kröller;Christoph Daniel;Florian Gunzer;E. Tolosano;Michael Bauer;Kerstin Amann;Stefan H Heinemann;S. Coldewey
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文献类型：
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作者：
Wiebke Pirschel;Antonio N. Mestekemper;B. Wissuwa;N. Krieg;Sarah Kröller;Christoph Daniel;Florian Gunzer;E. Tolosano;Michael Bauer;Kerstin Amann;Stefan H Heinemann;S. Coldewey
血栓性微血管病变、溶血和急性肾损害是溶血性尿毒症综合征(HUS)的典型临床特征，主要由产志贺毒素的大肠杆菌引起。在危及生命的感染中，即使全身溶血程度较低，游离态的血红素也会加重器官损害。因此，我们假设，血红蛋白和清除血红素的蛋白，结合珠蛋白和血凝素的存在分别影响HUS的预后和肾脏病理。在这里，我们研究了结合珠蛋白和血凝素缺乏症(结合珠蛋白-/-，血凝素-/-)和结合珠蛋白治疗HUS样病小鼠模型的效果。与野生型小鼠(71.4%)相比，结合珠蛋白-/-组小鼠的7天存活率降低了25%，而血凝素-/-组小鼠全部存活。志贺毒素攻击的血液连接蛋白-/-小鼠表现出肾脏炎症和血栓性微血管病变的减轻，这表明中性粒细胞募集和血小板沉积减少。这些观察结果与血凝素-/-小鼠超常的结合珠蛋白血浆水平有关。对志贺毒素攻击的野生型小鼠给予低剂量结合珠蛋白可减少肾脏的血小板沉积和中性粒细胞募集，这表明结合珠蛋白至少部分参与了有益的作用。志贺毒素攻击的野生型和结合珠蛋白-/-小鼠的溶血替代参数增加，而血红素加氧酶-1、铁蛋白和CD163等肝脏血红蛋白降解的迹象仅在志贺毒素攻击的野生型小鼠中增加。与这一观察结果一致，结合珠蛋白-/-小鼠显示管状铁沉积作为肾脏血红蛋白降解的指标。因此，结合珠蛋白和血凝素缺乏在志贺毒素介导的HUS中扮演着不同的角色，这表明结合珠蛋白参与了HUS的病理过程，而血凝素是多余的。
Thrombotic microangiopathy, hemolysis and acute kidney injury are typical clinical characteristics of hemolytic-uremic syndrome (HUS), which is predominantly caused by Shiga-toxin–producingEscherichia coli. Free heme aggravates organ damage in life-threatening infections, even with a low degree of systemic hemolysis. Therefore, we hypothesized that the presence of the hemoglobin- and the heme-scavenging proteins, haptoglobin and hemopexin, respectively impacts outcome and kidney pathology in HUS. Here, we investigated the effect of haptoglobin and hemopexin deficiency (haptoglobin-/-, hemopexin-/-) and haptoglobin treatment in a murine model of HUS-like disease. Seven-day survival was decreased in haptoglobin-/-(25%) compared to wild type mice (71.4%), whereas all hemopexin-/-mice survived. Shiga-toxin–challenged hemopexin-/-mice showed decreased kidney inflammation and attenuated thrombotic microangiopathy, indicated by reduced neutrophil recruitment and platelet deposition. These observations were associated with supranormal haptoglobin plasma levels in hemopexin-/-mice. Low dose haptoglobin administration to Shiga-toxin–challenged wild type mice attenuated kidney platelet deposition and neutrophil recruitment, suggesting that haptoglobin at least partially contributes to the beneficial effects. Surrogate parameters of hemolysis were elevated in Shiga-toxin–challenged wild type and haptoglobin-/-mice, while signs for hepatic hemoglobin degradation like heme oxygenase-1, ferritin and CD163 expression were only increased in Shiga-toxin–challenged wild type mice. In line with this observation, haptoglobin-/-mice displayed tubular iron deposition as an indicator for kidney hemoglobin degradation. Thus, haptoglobin and hemopexin deficiency plays divergent roles in Shiga-toxin–mediated HUS, suggesting haptoglobin is involved and hemopexin is redundant for the resolution of HUS pathology.